Arthropod maturation inhibitors

ABSTRACT

A number of terpenoid compounds and their epoxides were synthesized and found to prevent insect maturation when applied to insects in an immature stage of growth.

tlnied States Patent [1 1 Sehwni'z et al.

[ ee.3t,i974

[ ARTHROPOD MATURATION INHIBITORS [75] Inventors: Meyer Schwarz, Kensington; Philip E. Sonnet, Bowie; Nobel Wakabayashi, New Carrollton, all of Md.

[73] Assignee: The United States of America as represented by the Secretary of Agriculture, Washington, DC.

[22] Filed: Apr. 6, 1973 [21] App]. No.: 348,841

Related U.S. Application Data [62] Division of Ser. No. 104,781, Jan. 7, 1971.

[52] U.S. Cl 260/348 R, 424/DIG. 12, 424/278 [51] Int. Cl (307d N00 [58] Field oli Search 260/348 R Primary Examiner-Norma S. Milestone Attorney, Agent, or Firm-M. Howard Silverstein; Max D. Hensley; William E. Scott i 5 ABSTRA CT 2 Claims, No Drawings ARTHMUPUD MATURATHON HNHIBKTO This is a division of application Ser. No. 104,781, filed Jan. 7, 1971.

A non-exclusive, irrevocable, royalty-free license in the invention herein described, throughout the world for all purposes of the United States Government, with the power to grant sublicenses for such purposes, is hereby granted to the Government of the United States of America.

This invention relates to the control of arthropods, especially insects, and more particularly to compounds and to the preparation of compounds which exhibit ju-.

venile hormone activity by stimulation of larval development and inhibition of metamorphosis.

In view of the concern throughout the world regarding the persistence of many insecticides and insecticide residues in our environment and the potential hazard that these materials represent to human populations and furthermore, in view of the fact that many species of insect pests have become resistant or immune to insecticides, the need for more selective agents to meet the problems is evident.

Many of the substances that exhibit juvenile hormone activity possess a terpenoid skeleton. These compounds such as .farnesoi methyl ether and the juvenile hormone isolated from Hyalphoracecropia (L), methyl 10,1 l-oxido-3 ,l l-dimethyl-7ethyl trideca-2,6- dienoate, prevent the formation of sexually mature adults when applied at extremely low dosage levels either topically to the insect in the pupal stage or as a fumigant.

An object of this invention is to provide selective agents for control of insect pests.

Another object is to provide new chemical compounds that prevent insect maturation when applied to insects in an immature stage of growth.

In general, according to the presentinvention compounds of the general formula 11. is a number from 1 to 2;

on; M is JJ=CH -Ri R is a straight chain alkyl group of from one to two carbon atoms, a cycloalkyl group, a phenyl group, a

v substituted phenyl group, COOClri or CN; and R and R arestraight chain alkyl groups of from one to two carbon atoms, are synthesized and found to preventinwith an excess of an organo-lithium compound in which the organic group can be all-:yl, alkiriyl, alkynl or aryl. Compound 3 is then prepared by epoxidation of compound 1 with a peracid. Alternatively i may be prepared from using the Wadsworth-Emmons reaction (lAmer.

Chem. Soc. 83, 1733 (1971) to produce i XA/ Q/VKV The latter product may then be treated with either an organo-Mg-halogen (Grignard reagent) or an organo lithium compound to yield the desired compound 1 (the organic group is same as above). Compounds 5 and 7 are prepared from the appropriate amines,

2 R2 V Rs f M "W a u A \M and A g NH: NH?

respectively and the appropriate chloroformate ClCO0R,, (R as above), in the presence of a tertiary base such astriethylamine, which serves as a hydrogen chloride acceptor. The required amines are prepared by reduction of the oximesof the aldehydes.

R3 R2 R3 R2 and AMA HO \ClIO using lithium aluminum hydride [Helv. Chim. Acta. 37, 881 (1954)]. v

Again the epoxides 6 and 8 are readily prepared from the olefinic precursors 5 and 7 using peracid in an inert solvent. Compound 10 is prepared by the condensation with a malonic acid derivative in the presence of ammonium acetate (J. Amer. Chem. Soc. 63, 3452 (1941). Again, 11 is obtained by epoxidation of 10 using a peracid. I

The present invention provides a method for the control of insects, which comprises contacting the insects with one of the compounds in a sufficient amount to affect the normal development of said insects through their metamorphic stages. The materials may be ap- EXAMPLE 1.

1 1,12-epxy,

The mixture was allowed to stand overnight and then it was added to a large excess of cold water and extracted with hexane. The hexane extract was washed with water, dried and evaporated. The residue was fractionally distilled and yielded 15 g of farneson'itrile (bp 94-97 /0.2 mm) which was converted to Compound 1 as follows: To an ice cold solution of methyl magnesium iodide, prepared from magnesium (0.6 g) and methyl iodide (4.5 g) in 100 ml'anhydrous ethyl ether, was added dropwise 5.4 g farnesonitrile. After the addition was complete the reaction mixture was refluxed for 2 hours, allowed to stand overnight, and then decomposed by dropwise addition of excess aqueous ammonium chloride. The ether layer was evaporated and the residue was distilled to yield 3.0 g of Compound 1 bp l-ll0 1.4 mm. Compound 1 (200 mg) was treated at 0C with m-chloroperbenzoic acid (200 mg) in ml methylene dichloride to yield compound 3 after extraction of the m-chlorobenzoic acid with dilute aqueous sodium carbonate and removal of the methyl ene dichloride. The resultant product isv highly active against many insect species. Compound 3 can be further purified by distillation, gas-liquid or liquid-liquid chromatography. These processes however, do not enhance'the activity to a measurable extent.

EXAMPLE 2 Preparation of 3,7-Tetradecadien-2one, 11,12-epoxy- 8-ethyl-4,l2-dimethyl. (Compound 4). I

Methyl-3,1 l -dimethyl-7-ethyl-trideca-2,6,10- trienoate (Braun et al. J. Econ. Entomol. 61, 866 (1968) (2 g) was saponified with 1.5 g KOH in 50 ml 80 percent ethanol. The acid was isolated from the re-' action mixture by acidification and extraction with ether. An ether solution of the acid v(l g) was treated with an excess-of methyl lithium in hexane (5 ml of a 1.6 molar solution). The ketone, Compound 2 (0.5 g), was obtained after the reaction mixture was decomposed with an aqueous solution of ammonium chloride, followed by evaporation of theether and molecular distillation (100 (bath) /0.5 mm). Epoxidation and workup, as described in example 1, yielded Compound 4 which had extremely high juvenile hormone activity.

EXAMPLE 3 Preparation of carbamic acid, 3.-7dimethyl-6,7-epoxyethyl ester. (Compound 8).

3,7-Dimethyloct-6-enal (15.4 g) in 50 ml ethyl alchohol was added to a solution of hydroxylamine hydrochloride (7 g) and sodium carbonate (5 g) in 25 ml of water. The mixture was heated on the steambath for minutes and then allowed to cool. Addition of an ex cess of water yielded 3,7-dimethyl-oct-6-enal oxime as an oil. The oil was extracted with ether and the organic layer dried and evaporated. The residue was added dropwise to a solution of lithium aluminum hydride (3.8 g) in 380 ml anhydrous ethyl ether. After refluxing overnight an additional quantity of lithium aluminum hydride (0.78 g) was added to complete the reduction. Decomposition of the reaction mixture with excess aqueous sodium hydroxide (200 ml of 10 percent solution), separation of the ether layer, and distillation yielded 3,7-dimethyloct-6-enyl amine (10 g) bp 60 /0.5 mm). To an ice cold solution of this amine (1.5 g) and triethylamine (1.1 g) in ether (25 ml) was added dropwise a solution of ethyl chloroformate (1.1 g) in ether (10 ml). The reaction mixture was allowed to stand overnight at room temperature. The triethylamine hydrochloride was filtered off and the ether solution washed with water, dilute hydrochloric acid, and again with water. The other solution was dried and evaporated and the residue distilled to yield 2 g carbamic acid (3,7-dimethyl-6-octenyl)-, ethyl ester (Compound 7),'bp l02103/0.1 mm. The ester was epoxidized as described in the previous examples to yield V11. The crude reaction product can be readily purified by chromatography using neutral activated alumina.

EXAMPLE 4 Synthesis of 2 6-dodecadienoic acid, 2-cyano-l0,l1- dimethyl-, methyl ester (Compound 11).

Geranyl acetone (10 g), methyl cyano acetate (6 g), ammonium acetate (2 g) and acetic acid (1 ml) were refluxed in 200 m1 benzene using a Dean-Stark water separator. After 2 hoursof refluxing, one additional gram of ammonium acetate was added and the refluxing continued for 2 additiinal hours. The solution was cooled, washed with water and dried and then the solvent wasremoved. The residue was distilled to yield 2,6, lO-dodecatrienoic acid 2-cyano-3,7,1 l-trimethyl-, methyl ester (11 g), bp l30/.1 mm (Compound 10). Epoxidation of the above product as described previously yielded the compound 11.

EXAMPLE 5 mm. Epoxydation of the above as described previously yielded compound 12.

Juvenile Hormone Activity of Representativo Compounds on Tenebrio TABLE I-Continued I Juvenile Hormone Activity of Representative Compounds on Tenebrio molitor pupae molitor pupae Minimum weight @l'lliihli' ugJ c mpound needed 5 pound needed when applied top-i W pp 1 ically to pupae to wally to pupae to make the resultafll; make the osultant T il new? me 2 e0 Compound repr duction pound reproduction 1- v N O O O/\ H M 01 l 5 10. I C N 1. 0

WCOOCH 0. 03 O/ 1l /f\ ON 0.1 I o/ coocm I ll 0. 001 12 A CN 1. 0 /\/\/\/\4 ON I I Q N O 0 H ]l. A compound of the formula 0 m cm i o I ll 4: A y N o CH;;C-CH(CH2)1 =0H 0HQ) =CHC 0/ H i CH3 l H M... H V V V H m which R and R are methyl.

0 0'1 M 2. The compound of claim 1 in which R and R are H ethyl. =1: :9: 

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 in which R2 and R3 are ethyl. 